Anti-gastric ulcer chalcone ethers

ABSTRACT

Novel chalcone ethers of the formula   WHEREIN R1, R2, R3 and R4 are independently one selected from the group consisting of hydrogen atom and hydroxy, lower alkyl, lower alkoxy and acyloxy groups, and one of Z1 and Z2 is one selected from the group consisting of the groups represented by the formula (II),   THE OTHER OF Z1 and Z2 is one selected from the group consisting of the groups represented by the formula (II) and (III)   are useful compounds having remarkable anti-gastric ulcer activity and extremely low toxicity.

United States Patent [1 1 nu 3,928,421

Kyogoku etal. [451 Dec. 23, 1975 ANTI-GASTRIC ULCER CHALCONE 57 ABSTRACT ETHERS Novel chalcone ethers of the fonnula [75] inventors: Kazuaki Kyogoku, Tokyo; Katsuo Hatayama, Saitama; Sadakazu Yokomori; Teruya Seki, both of Tokyo, all of Japan [73] Assignee: Taisho Pharmaceutical 00., Ltd.,

Tokyo, Japan [22] Filed: June 25, I974 [21] Appl. No.: 483,004

[30] Foreign Application Priority Data wherein R., R R and R, are independently one se- Oct. 30, 1973 Japan ..4s-|z199 lectcd fmm the group Consislihg of hydrogen atom Jan. I9, I974 Ja an 49-8736 and y lower alkyl, lower alkoxy and acyloxy Jan. [9, 1974 Japan 49-8737 g oups. an ne of Z and Z, is one selected from the Feb. 9, 1974 Japan 49-16524 group consisting of the groups represented by the for mula (ll), [52] US. 260/479 R; 260/590 D; 424/331;

424/298 H: [5!] Int. Cl. C07C 69/02; C07C 49/84 [58 Field of Search 260/590, 590 D, 479 R E (n=1.2) [56] References Cited OTHER PUBLICATIONS the other of Z and L is one selected from the group Giu'iana et 8] Chem Abst vol. 68 page 066 consisting of the groups represented by the formula (ii) and (III) Jain et al., lndian .l. of Chem, Vol. ll, pp. 723-725 (1973). H Khanna, et al., Indian J, Vol. Chem, vol. ll, pp.

p i ja 0 Thomas Jr are useful compounds having remarkable anti-gastric Assmam y H Reamer ulcer activity and extremely low toxicity. Attorney, Agent, or Firm-Wenderoth, Lind & Ponack 21 (155 N D i ANTI-GASTRIC ULCER CHALCONE ETHERS BACKGROUND OF THE INVENTION 1. Field of the Invention Synthesized chalcone ethers having anti'gastric ulcer activity.

2. Description of the Prior Art Various chalcone derivatives are well known previously. These chalcone derivatives are reported to have various uses such as an oxidation inhibitor, radiation absorbent, anti-bacterial substance and sweetening agent.

On the other hand, some chalcone derivatives are reported as a pharmacologically active substance, for example, as analgesic, anti-inflammatory and vasodi lator agents.

As far as chalcone derivatives having an anti-gastric ulcer activity, however, there are only a few papers as follows:

Sophoradochromene; Japanese Pat. No. 623498, 2,2, 4,4-Tetrahydroxy-6'-methoxy-3'-(5-methyl-2- isopropenylhex-4-enyl)-chalcone; Japanese Pat. No. 69l783 and lsoliquiritigenin; Arzneimittel Forschung 17, 1544 The above Japanese patents disclose the extracting and isolating method of each compound from plants, said method are, however, always accompanied with some disadvantages such as complicated procedure, low yield and low purity.

BRIEF SUMMARY OF THE INVENTION This invention relates to novel chalcone ethers. More particularly, this invention concerns with novel chalcone ethers represented by the general formula (I) R3 coca OHC the other of Z and Z is one selected from the group consisting of the groups represented by the formulae (II) and (III) In this specification and claims, the term lower alkyl, lower alkoxy and acyloxy groups refer to each group having l-5 carbon atoms.

The object of the present invention is to provide novel chalcone derivatives possessing excellent antigastric ulcer activity together with low toxicity.

A further object of this invention is to provide novel useful chalcone derivatives by simple and convenient preparing procedure, especially by readily applicable procedure to manufacturing production.

The compounds of this invention may be prepared by condensation of substituted acetophenone with substituted benzaldehyde in alkaline or acidic condition followed by thermal rearrangement, if necessary, or by ether formation of substituted chalcone having at least one hydroxy group with alkenyl halide.

The compounds represented by the general formula (I) show remarkable anti-gastric ulcer activity which has not been observed in any other previous known anti-gastric ulcer agents. That is, the compounds of this invention show excellent effect for acetic acid ulcer which is analogous to chronic gastric ulcer as well as for various kinds of gastric ulcers such as stress ulcer, Shays ulcer and induced ulcers by drugs, for example, aspirin, steroids and other anti-inflammatory agents.

The merits of the compounds of this invention, that is, excellent anti-gastric ulcer activity and extremely low toxicity, are considered to be attributed to the combination of chalcone mother-structure and two substituted groups Z. and Z In other words, the definition that one of Z and Z is one selected from the group consisting of 3-methyl-2-butenyloxy and 3,7- dimethyl-Z,G-octadienyloxy groups, the other of Z, and Z is one selected from the group consisting of 3-methyI-Z-butenyloxy, 3,7dimethyl-2,6-octadienyloxy and 3-methyl-2-butenyl groups is most important factor in this invention. The other substituted groups, R R R and R are not so important as said groups 2 and 2,.

DETAILED DESCRIPTION OF THE INVENTION The compounds of this invention as defined in the formula (I) can be prepared by the following reaction sequence (I).

Condensation H In this reaction sequence (1), Z 2,, R R,, R and R, of the general formulae are same as defined above. Condensation of the compounds (IV) and (V) can be carried out by adding an alkali such as sodium hydroxide and potassium hydroxide or an .acid such as hydrochloric acid and sulfuric acid to a solution or a suspension of compounds (IV) and (V) in an organic solvent such as methanol, ethanol and ethyl acetate, and agitating the obtained mixture at 100C. for some hours or for a few days. Produced condensates (l) are separated from the mother liquor and are purified, if necessary, by distillation, recrystallization or column chromatography.

The compounds represented by the general formulae (IV) and (V) in which Z. or Z is 3-methyl-2- butenyloxy or 3,7-dimethyl-2,G-octadienyloxy group can be prepared by reaction of substituted acetophenone and substituted benzaldehyde, both having at least one hydroxy group, with 3-methyl-2-butenyl halide or 3,7-dimethyl-2,6-octadienyl halide in the presence of alkali.

0n the other hand, the compounds represented by the general formulae (IV) and (V) in which Z. or Z is 3-methyl-2-butenyl group can be synthesized by reaction of substituted acetophenone or substituted benzaldehyde with 3-methyl-2-butenyl halide, with 2-methyl- 3-butene-2-ol in the presence of boron trifluoride etherate or with 1,] -dimethyl-1r-allylnickel bromide, or by reaction of substituted acetophenone or substituted benzaldehyde, both having at least one hydroxy group, with 3-halogeno-3-methyl-l-butyne followed by reduction of obtained 1,l-dimethylpropargyl ether of each compound for obtaining l,l-dimethylallyl ether thereof, further followed by thermal rearrangement.

Further, almost all compounds of this invention (la) can be synthesized by the reaction process (2).

In this reaction sequence (2), one of X. and X is hydroxy group and the other of X. and X is one selected from the group consisting of hydroxy group and the above described groups (III) with the proviso X is not in the ortho-positions to acetyl group when X is hydroxy group, one of Y. and Y 2 is one selected from the group consisting of the above described groups (ll) and the other of Y. and Y is one selected from the group consisting of the above described groups (ll) and ([1]), each position of Y. and Y corresponding to each position of X. and X R. and R are independently one selected from the group consisting of hydrogen atom and lower alkyl, lower alkoxy and acyloxy groups, R.. and R are independently one selected from the group consisting of hydrogen atom and hydroxy, lower alkyl, lower alkoxy and acyloxy groups with the proviso R or R is only in the ortho-positions to acetyl group when R' or R is hydroxy group, and Hal is a halogen atom.

After condensation of the compounds (VI) and (VII) carried out in the same manner described in the reaction sequence l the condensates (Vlll) are dissolved in an organic solvent such as acetone, methanol and ethanol and reacted with the compounds (IX) in the presence of an alkali such as potassium carbonate, sodium carbonate, potassium hydroxide and sodium ethoxide at room temperature or a refluxing temperature for obtaining the objective compound (la).

The compounds (VI) and (V ll) may be prepared by reaction of substituted acetophenone or substituted benzaldehyde with 3-methyl-2-butenyl halide, with 2-methyl-3-butene-2-ol in the presence of boron trifluoride etherate or with l,l-dimethyl-1r-allylnickel bromide, or by reaction of substituted acetophenone or substituted benzaldehyde, both having at least one hydroxy group, with 3-halogeno-3-methyl-l-butyne followed by reduction of obtained l,l-dimethylpropargyl ether of each compound for obtaining l,l-dimethy- X X z Condensation fi RI Z l 4 1 COOH OHC v1 (VII) Ether Formation Y Y CH 2 1 1 1 Hal CH CHCCH H R g I n t i R 3 O R 2 n 1, Z

lallyl ether thereof further followed by thermal rearrangement.

In this reaction sequences (3A) and (3B), A, and A, are each l,l-dimethylallyloxy group, A, not being in 2' or 6' position, A and A are independently one selected from the group consisting of the above described groups (II), B and B are each hydroxy group, each position of B and 8' corresponding to each position of 30 A, and A,', C and C' are each 3-methyl-2-butenyl group being in each position neighboring to B and B, R",, R" and R" are independently one selected from the group consisting of hydrogen atom and hydroxy, lower alkyl, lower all-toxy and acyloxy groups with the proviso that R, does not neighbor to A when A, is in 2 or 6 position and simultaneously R", is not hydrogen atom.

The intermediate compounds (X) or (X') dissolved or suspended in an organic solvent, for example, diethylaniline, dimethylformamide, dibutylamine, aniline or hexadecylamine or the compounds as they are without solvent, are heated at 200C. for several hours under or not under nitrogen atmosphere to afford the objective compounds (lb) and (10).

The compounds represented by the general formulae (X) and (X') can be prepared by condensation of substituted acetophenone with substituted benzaldehyde one of which is substituted by l,l-dimethylallyloxy group, the other of which is substituted by 3-methyl-2- butenyloxy or 3,7-dimethyl-2,6-octadienyloxy group, by condensation of substituted acetophenone with substituted benzaldehyde one of which is substituted by l,l-dimethylpropargyloxy group, the other of which is substituted by 3-methyl-2-butenyloxy or 3,7-dimethyl- 2,6-octadienyloxy group, followed by reduction of 1,]- dimethylpropargyloxy group in the obtained condensate to l,l-dimethylallyloxy group therein, or by reaction of substituted chalcone having 3-methyl-2- butenyloxy or 3,7-dimethyl-2,-octadienyloxy group and at least one of hydroxy group with 3-halogeno-3- methyl-l-butyne, followed by reduction of l,l-dimethylpropargyloxy group in the obtained substituted chalcone to 1,l-dimethylallyloxy group therein.

The compounds of this invention showed an excellent preventive or curative effect to the various types of experimental gastric ulcers in rats. That is, the present compounds accelerated the healing process of the chronic gastric ulcers induced by injection of acetic acid (acetic acid ulcer), inhibited ulcers and erosions formed by ligation of pylorus (Shays ulcer) or by stressing animals by means of restraint and water immersion (stress ulcer) and also inhibited ulcer and erosions induced by administration of aspirin (aspirin ulcer). As general pharmacological activity, any unfavorable side effects have not yet observed in central nervous system and autonomic nervous system by the administration of the present compounds.

The compounds of this invention are effective to tion of injured gastric mucosal tissue, prevent gastriculcer from occurring or from recurring and exhibit excellent healing effect to previously existing gastric ulcer. Further, the present compounds have weak suppresive activity to secretion of an aggressive factor to ulcer, such as hydrochloric acid or pepsin, however, do not show such side effects as observed in the administration of anti-cholinergic drugs.

ln-the present compounds, 3-methyl-2-butenyl group unit, is considered to play an important role in mucosal resistance and tissue reparative activities. Thus, the compounds of this invention exhibit an excellent antigastric ulcer activity just by themselves, however, may be administered together with any other drugs, if necessary.

The toxicity of the present compounds is extremely low and no death was observed within 96 hours in mice and rats by administration of 5 g/Kg orally or 2 g/Kg intra-peritoneally, therefore, the compounds can be administered safely for long period without accompaning any side effects.

The compounds of this invention may be administered orally or parenterally for gastric and duodenal ulcers, gastric hyper acidity, acute and chronic gastritis, chronic constipation, chronic diarrhea, hypo gastralgia and any other gastric diseases. Dose for human; 20-150 mg/body.

As the especially useful compounds among the compounds represented'by the general formula (I), the following compounds are described here, but are not intended as a limitation thereof.

T 3 c owlcu H c (JP-152B O 3 OCH3 HO cm H C-i-CHCI-I H b.p.l31 -133.sc. (0.09 mmHg) 4' -hydroxy-Z', 4-dimethoxy-3'-(3methyl-Z-butenyl)-2-(3, 7-dimethyl-2, 6-

octa dienyl oxy) chalcone 3 OCH OCH b.p. 122" 125C. (0. 08 mmHg) 2', 4, 4'-trimethoxy- 3' -(3-methyl-2-butenyl)-Z-(3, T-dimethyl-Z, 6-

octadieny1oxy)chalcone The following examples are illustrative of the present invention with further details and do not mean any limitation. In these examples, g" signifies grams, and ml" signifies milliliters.

EXAMPLE I A suspension of 218 mg of 4-(3-methyl-2-butenyloxy)acetophenone (IV) and 200 mg of 4-(3-methyl-2- butenyloxy)-benzaldehyde (V) in 8 ml of ethanol was A mixture of g of 4,4'-dihydroxychalcone (Vlll) in ml of acetone and 6.5 g of potassium carbonate was added with 8.5 g of 3-methyl-2-butenyl bromide (1X) whilst stirring and was agitated for 1 hour at room temperature. After filtration of potassium carbonate, almost all amount of acetone was evaporated. The

residue was added with 300 ml of ether and further added with each 50 ml of 1% potassium carbonate solution three times to transfer unreacted 4,4'-dihydroxychalcone to water layer. The ether layer was washed with water, dried with anhydrous sodium sulfate and filtered. After removal of ether, the obtained residue was recrystallized with a mixture of acetone and methanol to afford 5.9 g of 4,4-bis-(3-methyl-2- butenyloxy)chalcone (1), mp. 96C.

EXAMPLE 3 A solution of3 g of salicylaldehyde in 20 ml of acetone was added with 4.1 g of potassium carbonate and 4.9 g of 3-methyl-2-butenyl bromide, then was agitated for 2 hours at room temperature to give 3.5g of 2-(3- *is methyI-Z-butenyloxy)benzaldehyde (V).

To a solution of 3.3 g of p-(3-methyl-2-butenyloxy)acetophenone (1V) and 3.0 g of obtained 2-(3-methyl-2-butenyloxy)benzaldehyde (V) in ml of ethanol, 30 ml of 50% potassium hydroxide solution was added, then the mixture was agitated for 3 hours at room temperature. After addition of 200 ml of water, the reaction mixture was acidified with hydrochloric acid, extracted with ether. The ether layer was distilled under reduced pressure to give 3.6 g of 2,4'-bis-(3-methyl'2- butenyloxy)chalcone (2), b.p. 108 110C. (0.1 mmHg), m.p. 63C.

EXAMPLE 4 A solution of 3.3 g of p-( 3-methyl-2-butenyloxy)acetophenone (1V) and 3.0 g of m-(3-methyl-2- butenyloxy)benzaldehyde (V) in 5 ml of ethanol was added with 30 ml of 50% potassium hydroxide solution and was agitated for 3 hours at room temperature. After addition of water, the reaction mixture was acidified with hydrochloric acid and extracted with ether. The ether layer was distilled under reduced pressure to give 3.1 g of 3,4'-bis-(3-methyl-2-butenyloxy)chalcone (3), b.p. 111 112C. (0.1 mmHg).

EXAMPLE 5 A suspension of 260 mg of 2-hydroxy-4-(3-methyl-2- butenyloxy)acetophenone (1V) and 219 mg of 4-(3- methyl-Z-butenyloxy)benzaldehyde (V) in 8 ml of ethanol was added with 3 m1 of 50% potassium hydroxide solution and was agitated for I hour at room temperature. After the reaction mixture was acidified with hydrochloric acid, the solvent was evaporated. The obtained residue was extracted with each 30 ml of ether three times and the ether layer was separated, washed with water and dried with anhydrous sodium sulfate. After evaporation of ether, the residue was distilled under reduced pressure to give 390 mg of 2'-hydroxy-4,4'-bis-(3-methyl-2-butenyloxy)chalcone (4), b.p. 109 114C. (0.1 mmHg).

EXAMPLE 6 To a mixture of 5 g of 2,4,4'-trihydroxychalcone (Vlll) in 80 ml of acetone and 6.6 g of potassium carbonate, 8.7 g of 3-methyl-2-butenyl bromide (1X) was added dropwise whilst stirring, then the mixture was agitated for 3 hours at room temperature. After potassium carbonate in the reaction mixture was filtered off, almost all amount of acetone was evaporated. To the obtained residue, 300 ml of ether was added and further each 50 ml of 1% potassium hydroxide solution was added three times to transfer unreacted 2',4,4'4,- 4'-trihydroxychalcone (Vlll) into water layer. The ether layer was washed with water, dried with anhydrous sodium sulfate and filtered successively. Ether was evaporated off and the obtained residue was recrystallized from acetone-methanol mixture to give 5.3 g of 2'-hydroxy-4,4'-bis-(3-methyl-2-butenyloxy)chalcone (4), m.p. 87 885C.

EXAMPLE 7 To a mixture of 5 g of 2,2',4'-trihydroxychalcone (Vlll) in 50 ml of methanol and 10 g of sodium carbonate, 14 g of 3-methyl-2-butenyl chloride (IX) was added dropwise whilst stirring, then the mixture was refluxed for 1 hour. After sodium carbonate was filtered off, methanol was evaporated. The obtained residue was extracted with ether, washed with water and 16 dried with anhydrous sodium sulfate successively. Then, ether was evaporated off and the residue was distilled under reduced pressure giving 4.7 g of 2'- hydroxy-Z ,4 '-bis-( 3-methyl-2-butenyloxy )chalcone (5), b.p. 112C. (0.1 mmHg).

EXAMPLE 8 A solution of 130 mg of 2-methoxy-4-(3-methyl-2- butenyloxy)acetophenone (IV) and mg of p-(3- methyl-Z-butenyloxy)benzaldehyde (V) in 2 ml ofethanol was added with 3 ml of 50% potassium hydroxide solution and was agitated at room temperature for 1 hour. After the reaction mixture was acidified with dilute hydrochloric acid, the solvent was evaporated off. The obtained residue was extracted with ether and the ether layer was washed with water and dried with anhydrous sodium sulfate. After removal of ether, the residue was distilled under reduced pressure to give mg of 2-methoxy-4,4'-bis-(3-methyl-2-butenyloxy)chalcone (6), b.p. 117 119C. (0.09 mmHg).

EXAMPLE 9 To a solution of4l 8 mg of 4-hydroxy-3-(3-methyl-2- butenyl)acetophenone (1V) and 390 mg of 4-(3-methyl-2-butenyloxy)benzaldehyde (V) in 2 ml of ethanol, 20 ml of 50% potassium hydroxide solution was added, then the mixture was agitated for 3 hours at room temperature. After addition of water, the reaction mixture was acidified to PH 2 with dilute hydrochloric acid and extracted with ether. The solvent was evaporated off and the obtained residue was column chromatographed on silica gel with acetone-hexane mixture affording 3 10 mg of colorless powder, 4-hydroxy-3-(3-methyl-2- butenyl)-4-(3-methyl-2butenyloxy)chalcone (7), m.p. 145 147C.

EXAMPLE [0 A solution of 6.0 g of p-(1,l-dimethylallyloxy)acetophenone and 6.1 g of p-(3-methyl-2-butenyloxy)benzaldehyde in 25 ml of ethanol was added with 230 g of 50% potassium hydroxide solution and was agitated at room temperature for 3 hours. The obtained condensate, 9.8 g of 4'-(1,1-dimethylal1yloxy)-4-(3- methyl-Z-butenyloxy)chalcone (X') was dissolved in 70 ml of diethylaniline and was agitated at C. for 4 hours under nitrogen atmosphere. I

As a result, 8.8 g of 4'-hydroxy-3'-(3-methyl-2- butenyl )-4-(3-methyl-2-butenyloxy)chalcone (7), m.p. l47C., was obtained.

EXAMPLE 1 l A solution of 5.8 g of p-(1,1-dimethylpropargyloxy)acetophenone and 6.0 g of p-( 3-methyl-2-butenyloxy)benzaldehyde in 15 ml of ethanol was added with 200 g of 50% potassium hydroxide solution and was agitated at room temperature. The obtained condensate, 7.7 g of 4'-(1,1-dimethylpropargyloxy)-4-(3-rnethyl-2- butenyloxy )chalcone was dissolved in 75 ml of benzene and was hydrogenated by addition of 1.5 g of Lindlar catalyst to get 7.5 g of 4'-(l,1-dimethyla1lyloxy)-4-(3- methyl-Z-butenyloxy)chalcone (X'), b.p. l25- 126C. (0.1 mml-lg). Then, 7.4 g of the same compound was dissolved in 50 ml of diethylaniline and was agitated at 140C. for 3 hours under nitrogen atmosphere. Recrystallization of the obtained compound from acetonehexane mixture gave 5.8 g of 4'-hydroxy-3'-(3-methyl- Z-betenyl )-4-( 3-methyl-2-butenyloxy )chalcone (7 m.p. l45-147C.

EXAMPLE 12 To a suspension of 440 mg of 2,4-dihydroxy-3-(3- methyl-2-butenyl)acetophenone (1V) and 380 mg of p-(3-methy1-2-butenyloxy )benzaldehyde (V) in 2 ml of ethanol, 8 ml of 40% potassium hydroxide solution was added, then the mixture was agitated for 72 hours at room temperature. After addition of water, the reaction mixture was acidified to pH 2 with dilute hydrochloric acid and extracted with ether. The solvent was evaporated off and the obtained residue was column chromatographed on silica gel with benzene to give 95 mg of yellow needles, 2',4-dihydroxy-3'-(3-methyl-2- butenyl)-4-(3-methyl-2-butenyloxy)chalcone (8), m.p. 167 168.5C.

EXAMPLE 13 A solution of 6.4 g of 2-hydroxy-4-(1,1-dimethylpropargyloxy)acetophenone and 5.4 g of p-(3-methyl- 2-butenyloxy)benzaldehyde in 25 ml of ethanol was added with 234 g of 50% potassium hydroxide solution and was agitated at room temperature for 8 hours. The obtained condensate, 8.5 g of 2'-hydroxy-4-(3-methyl- 2-butenyloxyl)-4'-( l ,1-dimethylpropargyloxy)chalcone was dissolved in 85 ml of benzene and was hydrogenated by addition of 1.7 g of Lindlar catalyst to give 8.4 g of 2'-hydroxy-4-(l,1-dimethyla1ly1oxy)-4-(3- methyI-Z-butenyloxy)chalcone (X') b.p. 122 124C. (0.09 mmHg). The obtained compound in 8.3 g was dissolved in 60 ml of diethylaniline and was agitated at 130C. for 4 hours under nitrogen atmosphere.

After recrystallization of the obtained compound from acetone-hexane mixture, 5.5 g of 2,4-dihydroxy- 3 3 -methy1-2-butenyl )-4-( 3-methy1-2-buteny1oxy chalcone (8), m.p. 167 168.5C., was obtained.

EXAMPLE 14 A solution of 7.3 g of 2',4'-dihydroxy-4-(3-methyl-2- buteny1oxy)chalcone and 3.5 g of potassium carbonate in 45 ml of dimethylformamide was agitated at room temperature for 3 hours under nitrogen atmosphere, then was heated at 80C. and added with 5.7 g of 3- chloro-3-methyl-1-butyne dropwise whilst stirring. Agitation of the mixture was further continued for 7 hours at the same temperature. The obtained 2.9 g of 2'- hydroxy-4-(3-rnethyl-2-butenyloxy)-4-(1,1-dimethyl' propargyloxy)chalcone was dissolved in 40 ml of hen zene and was hydrogenated in the presence of 0.3 g of Lindlar catalyst for obtaining 2.88 g of 2'-hydroxy-4'- (1,1 -dimethyla1lyloxy )-4-(3-methyl-2-butenyloxy c-halcone (X'). The whole amount of this compound was dissolved in 75 ml of diethylaniline and was agitated at 130C. for hours under nitrogen atmosphere to afford 2.1 l g of 2,4' -dihydroxy-3'-(3-methy1-2- butenyl)-4-(3-methyl-2-buteny1oxy)chalcone (8), m.p. 167 168.5C.

EXAMPLE 15 To a suspension of 660 mg of 2,4-dihydroxy-5-(3- methyl-2-butenyl)acetophenone (IV) and 571 mg of p-(3-methyl-2-butenyloxy)benzaldehyde (V) in 3 ml of ethanol, 12 ml of 40 potassium hydroxide solution was added, then the mixture was agitated for 1 hour at 60C. The same process as Example 12 was carried out to give 280 mg of orange needles, 2',4'-dihydroxy-5'- (3-methyl-2-butenyl)-4-(3-methyl-2-butenyloxy)chalcone (9), m.p. 145 146C.

EXAMPLE 16 A solution of 9.9 g of 2,4-diacetoxy-3-(3-methyl-2- butenyl)acetophenone (1V) and 9.6 g of 2-methyl-4- (3-methy1-2-buteny1oxy)benzaldehyde (V) in 160 m1 of anhydrous ethyl acetate was saturated with hydrogen chloride gas at 0C. and was agitated for 12 hours at the same temperature. Then, the solvent was evaporated off on water bath. After cooling, the obtained residue was dissolved in ether and the ether solution was washed with water and dried with anhydrous sodium sulfate, then, ether was removed by evaporatiomThe obtained residue was charged on silica gel column and eluted with acetone-hexane mixture to afford 2.1 g of 2',4'-diacetoxy-2-methyl-3 3-methyl-2-butenyl )-4- (3-methyl-2-butenyloxy)chalcone (10), b.p. 130 133C. (0.08 mmHg).

EXAM PLE 1,7

A suspension of 170 mg of 4-(3-methyl-2-butenyloxy)acetophenone and 159 mg of 4-( 1 ,l-dimethylpropargyloxy)benzaldehyde in 8 m1 of ethanol was added with 3 ml of 50% potassium hydroxide solution and was agitated for 1 hour at room temperature. After the reaction mixture was acidified with hydrochloric acid, the solvent was evaporated off. The obtained residue was extracted with each 30 ml of ether three times. The ether layer was washed with water and dried with anhydrous sodium sulfate. After evaporation of ether, the residue was distilled under reduced pressure to give 247 mg of 4-(1,1-dimethylproparglyoxy)-4'-(3 methyl- 2-butenyloxy)chalcone, b.p. 109 113C. (0.06 mmHg).

To a suspension of 240 mg of thus obtained compound in 7 ml of benzene, 50 mg of Lindlar catalyst was added and the mixture was agitated for 1 hour to hydrogenate the compound. After the filtration of the reaction mixture, benzene was removed by evaporation giving 4-(1,1-dimethy1ally1oxy)-4'-(3-methy1-0385 2- butenyloxy)chalcone (X), to which 10 ml of diethylaniline was added. -rnethyl- The mixture was agitated for 5 hours at C. After cooling, the reaction mixture was poured into ice-cooled dilute hydrochloric acid to get acidic condition and extracted with ether. The extract was washed with dilute hydrochloric acid, water and saturated sodium chloride solution successively, and dried with anhydrous sodium sulfate. Ether was removed by evaporation and the obtained residue was distilled under reduced pressure to afford 155 mg of 4-hydroxy-3-(3-rnethyl-2-butenyl)-4'-(3-methyl-2- buteny1oxy)chalcone (11). b.p. 132C. (0.02 mmHg), m.p. 139.5 140.5C.

EXAMPLE 18 A solution of 6.2 g of 2-hydroxy-4-(3-methyl-2- butenyloxy)acetophenone and 5.2 g of p-( 1 ,l-dimethylallyloxy)benzaldehyde in 25 ml of ethanol was added with 230 g of 50% potassium hydroxide solution and was agitated at room temperature for 6 hours. The obtained condensate, 8.8 g of 2-hydroxy-4-(1,1-dimethy1al1yloxy)-4'-( 3-methyl-2-butenyloxy)chalcone (X) was dissolved in 60 ml of diethylaniline and was agitated at 130C. for 4 hours under nitrogen atmosphere. After recrystallization of the obtained compound from acetone-hexane mixture, 7.1 g of 2',4-dihydroxy-3-(3- methyl-2-butenyl)-4'-(3-methy1-2-butenyloxy)chalcone (12), m.p.142143C., b.p. 147C. (0.11 mmHg), was obtained.

A solution of 3.1 g of 2-hydroxy-4-(3-methyl-2- butenyloxy)acetophenone (1V) and 3.2 g of 4- methoxy-3-(3-methyl-2-butenyl)benzaldehyde (V) in 6 ml of ethanol was added with 30 ml of 50% potassium hydroxide solution and was agitated for 3 hours at room temperature. After the reaction mixture was acidified with dilute hydrochloric acid, the solvent was evaporated off. The obtained residue was extracted with ether and the ether layer was washed with water and dried with anhydrous sodium sulfate. After removal of ether, the resulting residue was recrystallized from methanol-acetone mixture to give 4.7 g of yellow needles of 2'-hydroxy-4-methoxy-3-(3-methyl-2- butenyl )-4'-( 3-methyl-2-butenyloxy)chalcone (13), mp. 91 92C.

EXAMPLE 20 A solution of 3.2 g of 2-methoxy-4-(3-methyl-2- butenyloxy)acetophenone (1V) and 3.4 g of 2-hydroxy- 4-methoxy-3-(3-methyl-2-butenyl)benzaldehyde (V) in 6 ml of ethanol was added with 30 ml of 50% potassium hydroxide solution and was agitated for 3 hours at room temperature. After the reaction mixture was acidified with dilute hydrochloric acid, the solvent was evaporated off. The obtained residue was extracted with ether and the ether layer was washed with water and dried with anhydrous sodium sulfate. After removal of ether, the residue was distilled under reduced pressure to give 4.5 g of 2-hydroxy-2,4-dimethoxy-3- (3-methyl-2-butenyl)-4'-(3-methyl-2-butenyloxy) chalcone (l4), b.p. 131 133C. (009 mmHg).

EXAMPLE 21 A solution of 7.6 g of 2,6-dimethoxy-4-(3-methyl-2- butenyloxy)acetophenone (1V) and 7.0 g of 4-acetoxy- 3-(3-methyl-2-butenyl)benzaldehyde (V) in 140 ml of anhydrous ethyl acetate was added with 40 ml of 40% sulfuric acid solution and was agitated for 6 hours at C. After the solvent was evaporated off, the obtained residue was added with water and was extracted with ether. The extract was washed with water, dried with anhydrous sodium sulfate, then ether was evaporated off. The obtained residue was distilled under reduced pressure to afford 1.9 g of 4-acetoxy-2',6'-dimethoxy- 3-(3-methyl-2-butenyl)-4'-(3-methy1-2-butenyloxy)- chalcone (15), b.p. 129 131C. (0.09 mmHg).

EXAMPLE 22 A solution of 2.7 g of p-(3,7-dimethyl-2,6- octadienyloxy)acetophenone (IV) and 2.6 g of p-(3,7- dimethyl-2,6-octadienyloxy)benzaldehyde (V) in 10 ml of ethanol was added with 30 ml of 50% sodium hydroxide solution and was agitated for 1 hour at 50C. After addition of cold water, the reaction mixture was acidified with hydrochloric acid and extracted with ether. The ether layer was distilled under reduced pres sure to give 3.2 g of 4,4-bis-(3.7-dimethyl-2,6- octadienyloxy)chalcone (16), b.p. 1 14 116C. (0.06 mmHg), m.p. 69 70C.

EXAMPLE 23 To a mixture of 3 g of 4,4'-dihydroxy-3'-methylchalcone (Vlll) in 60 ml of acetone and 3.9 g of potassium carbonate, 15 g of 3,7-dimethyl-2,6-octadieny1 bromide (1X) was added dropwise whilst stirring, then the mixture was agitated for 3 hours at room temperature.

After the reaction mixture was filtered to remove sodium carbonate, acetone was evaporated off. The obtained residue was extracted with ether and the ethereal layer was washed with water and dried with anhydrous sodium sulfate. Ether was removed by evaporation and the obtained residue was distilled under reduced pressure to give 4.5 g of 3'-methyl-4,4'-bis-(3,7- dimethyl-2,6-octadienyloxy)chalcone (17), b.p. 1 19 121C. 0.1 mmHg).

EXAMPLE 24 A solution of 3.3 g of 4'-hydroxy-4-methoxy-2-(3,7- dimethyl-2,6-octadienyloxy)chalcone and 5.5 g of potassium hydroxide in 23 m1 of dimethylformamide was added dropwise with 4.2 g of 3-bromo-3-methyl-1- butyne under heating at C. whilst stirring and was agitated for 7 hours at the same temperature. The obtained 1.7 of 4-methoxy-2-(3,7-dimethyl-2,6- octadienyloxy)-4'-(1,1-dimethylpropargyloxy)chalcone was dissolved in 25 m1 of benzene and was hydrogenated in the presence of 0.2 g of Lindlar catalyst to give 1.6 g of 4-methoxy-4-(1,l-dimethylallyloxy)-2- (3,7-dimethyl-2,6-octadienyloxy)chalcone (X'). The whole amount of this compound was dissolved in 45 ml of diethylaniline and was agitated at 140C. for 5 hours under nitrogen atmosphere to afford 1.3 g of 4- hydroxy-4-methoxy-3' (3-methyl-2-butenyl)-2-(3,7- dimethyl-Z,6-octadienyloxy)chalcone (18 b.p. 133- 135C. (0.09 mmHg).

EXAMPLE 25 A solution of 6.1 g of 2-methoxy-4-(1,1-dimethylpropargyloxy)acetophenone and 8.3 g of 4-methoxy-2- (3,7-dimethyl-2,6-octadienyloxy)benzaldehyde in 20 ml of ethanol was added with 220 g of 50% potassium hydroxide solution and was agitated at 60C. for 1 hour. The obtained condensate, 9.2 g of 2,4-dimethoxy-2-(3,7-dimethyl-2,6-octadienyloxy)-4-( 1,1- dimethylpropargyloxy)chalcone was dissolved in ml of benzene and was hydrogenated in the presence of 1.9 g of Lindlar catalyst for obtaining 9.1 g of 2,4- dimethoxy-4-(1,1-dimethylallyloxy)-2-(3,7-dimethyl- 2,6-octadienyloxy)chalcone (X'). Whole amount of this compound was dissolved in 65 m1 of diethylaniline and was agitated at 150C. for 5 hours under nitrogen atmosphere to afford 5.1 g of 4-hydroxy-2',4-dimethoxy-3'-(3-methyl-2-butenyl)-2(3,7-dimethyl-2,6- octadienyloxy)chalcone (19), b.p. 131 133.5C. (0.09 mmHg).

EXAMPLE 26 A solution of 3 g of 2,4-dimethoxy-3-(3-methyl-2- butenyl)acetophenone (1V) and 3.5 g of 4-methoxy-2- (3,7-dimethyl-2,6-octadienyloxy)benzaldehyde (V) in 10 ml of methanol was added with 40 ml of 50% potassium hydroxide solution and was agitated for 3 hours at room temperature. After addition of water, the reaction mixture was acidified with hydrochloric acid and extracted with ether. The extract was distilled under reduced pressure to give 3.7 g of 2',4,4'-trimethoxy-3'- (3-methyl-2-butenyl)-2-(3,7-dimethyl-2,6- octadienyloxy)chalcone (20), b.p. 122 125C, (0.08 mmHg).

EXAMPLE 1 Acute toxicity of the compounds was investigated in male rats of Wyster strain weighing to g and in male mice of ddy strain weighing 13 to 15 g. A single 21 dose of g/Kg orally or 2 g/Kg intra-peritoneally was administered in mice and rats. Then, animals died within 96 hours after administration were counted. A degree of acute toxicity was expressed as mortality rate (animals died X 100 animals used). Obtained mortality rate of each compound was zero.

EXAMPLE ll Anti-gastric ulcer activities of the present com pounds were tested according to Takagis acetic acid ulcer method (Japanese Journal of Pharmacology i9, 418 (1969)).

Male rats of Donryu strain weighing 230 to 250 g were used for screening curative effect of the present compound on chronic gastric ulcers induced by means of submucosal injection of acetic acid.

Animals were laparotomized under ether anesthesia and injected with 0.0] ml of 20% acetic acid between the serosa and the muscular layer of the pyloric antrum. After surgery, the abdomen was closed and animals were fed normally. The testing drugs were perorally administered twice in a day for ten days from two days after the operation and animals were sacrificed at twelfth day from the operation in order to assess the healing process of the ulcer. Each stomach was removed, filled with l5 ml of l% formalin solution and placed in the same solution for about minutes to fix the outer layer of the gastric wall according to Brodies method (Gastroenterology 38, 353 (1960)).

Then, the stomach was cut open along the greater curvature and examined grossly for lesions. The area of the produced ulcer was designated as ulcer index.

Using the ulcer index, curative ratio of ulcer was calculated from the following equation:

Curative ratio 100 (C- S)/C, wherein C is ulcer index of control, S is ulcer index of sample.

In Table 1, obtained curative ratio of each compound was shown.

EXAMPLE Ill Another anti-gastric ulcer activity test was conducted by Shays ulcer method (Gastroenterology 5, 43 (1945)).

Male rats of Donryu strain weighing 200 to 230 g were used for screening the preventive effect of the present compound to so-called Shays ulcer produced by ligation of pylorus. Preceeding the operation, animals fasted for 48 hours except water ad libitum. Under ether anesthesia, mid ventral line of the animal was incised and the pylorus was ligated. Then, the abdomen was closed and the testing drugs were administered intraperitoneally. After hours from the operation, animals were killed by ether. The esophagus was ligated and the stomach was carefully removed. Volume of gastric juice was measured and lesions at the portion of the forestomach were macroscopically examined. The areas of ulcers and erosions were measured and the sum of both was designated as ulcer index.

22 Using ulcer index, preventive ratio of ulcer was calculated from the following equation:

Preventive ratio (C S)/C.

wherein C is ulcer index of control, S is ulcer index of sample.

In Table I, obtained ulcer index of each compound was summarized, together with preventive ratio of gastric juice secretion which was calculated by the same manner as preventive ratio of ulcer.

EXAMPLE IV Anti-gastric ulcer activity of the present compounds was investigated by Takagis stress ulcer method (Japanese Journal of Pharmacology l8, 9 (1968)).

Male rats of Donryu strain weighing 260 to 300 g were used for screening preventive effect of the present compound to gastric ulcer produced by means of restraint and water immersion.

Animals were placed and immobilized in the stress cage and immersed vertically to the xyphoid of the animal in a water bath at 23C. for 7 hours. The testing drugs were intra-peritoneally administered 30 minutes before the restraint.

At the end of the stress period, animals were removed from water bath, released from the stress cage and kill by a blow. The stomach was removed and inflated with 15 ml of 1% formalin solution and placed in the same solution for about 10 minutes to fix the outer layer of the gastric wall according to Brodies method. Then, the stomach was cut open along the greater curvature and lesions were examined macroscopically. The areas of ulcers and erosions were measured and the sum of both was designated as ulcer index.

From the equation described in Example lll, each preventive ratio was calculated and indicated in Table 1.

EXAMPLE V Selecting aspirin as a drug which often brings about gastric ulcers, anti-gastric ulcer activity of the present compound was investigated.

Male Donryu strain rats weighing 200 to 300 g were used for the examination of preventive effect to aspirininduced gastric ulcers.

Animals were treated by aspirin administration of each 200 mg/Kg perorally in three times at 2 hours interval. The testing drugs were perorally administered 30 minutes before an initial aspirin administration. Two hours later from final aspirin administration, animals were sacrificed by a blow and each stomach was removed and inflated with about l5 ml of 1% formalin solution and placed in l formalin solution. Ten minutes later, the stomach was cut open along the greater curvature and the areas of ulcers and erosions were measured. The sum of both was designated as ulcer index and each preventive ratio was calculated by the same manner as described in Example ll and was shown in Table l.

Table Curative Ratio of Acetic Acid Ulcer. Preventive Ratio of Shays Ulcer. Stress Ulcer, Aspirin-induced Ulcer and Preventive Ratio of Gastric Juice Secretion in the Case of Shays Ulcer in Rat Curative Preventive Ratio of Number Ratio of Gastric Juice Com Dose of Acetic Acid Secretion in the Shay's Stress Aspirin pound N0. (mg/Kg) Animals Ulcer Case of Shays Ulcer Ulcer Ulcer Ulcer(%) 100 6 29.1 83.7

50 10 75.0 30.9 59.0 89.5 I 20 10 55.1 21.8 44.8 69.5 l 10 44.4 25.5 40.6 75.9 50 7 25.5 94.1 2 3O 7 95.1 60.3

50 I0 L] 23.6 78.2 83.6 4 20 27.7 25.5 66.1 68.6 l0 H) 20.0 43.5 37.3

5 6 16.4 80.3 50 5 52.7 98.5 1 l 50 7 21.8 82.8 I2 50 5 2l.4 76.7 16 5O 7 23.6 63.2

What we claim is: l. A chalcone ether represented by the formula (I) wherein R,, R R and R are independently a member selected from the group consisting of hydrogen, hydroxy, alkyl of l-5 carbons, alkoxy of 1-5 carbons and alkanoyloxy of l-S carbons and one of Z and Z is a member selected from the group consisting of the groups represented by the formula (ll) wherein n is l or 2 and the other of Z and Z is a member selected from the group consisting of the groups represented by the formula (ll) and (Ill) 1" CH,CH CH,

(Ill) 8. A chalcone ether according to claim 1, 4'- hydroxy-3 3-methyl-2-butenyl )-4-( 3-methyl-2- butenyloxy)chalcone.

9. A chalcone ether according to claim I, 2,4'-dihydroxy-3 '-(3-methyl-2-butenyl )-4-( 3-methyl-2-butenloxy)chalcone.

10. A chalcone ether according to claim I, 2',4'- dihydroxy-S'-(3-methyl-2-butenyl)-4-(3-methyl-2- butenyloxy)chalcone.

11. A chalcone ether according to claim 1, 2',4- diacetoxy-2-methyl-3 3-methyl-2-butenyl )-4-( 3- methyl-Z-butenyloxy)chalcone.

12. A chalcone ether according to claim 1, 4- hydroxy-3 3-methyl-2-butenyl )-4 3-methyl-2- butenyloxy)chalcone.

13. A chalcone ether according to claim I, 2', 4-dihydroxy-3-( 3-methyl-2-butenyl )-4 3-me thyl-2- butenyloxy)chalcone.

14. A chalcone ether according to claim 1, 2- hyd roxy-4-methoxy-3-( 3-methyl-2-butenyl )-4 3- methyl-Z-butenloxy)chalcone.

15. A chalcone ether according to claim I, 2- hydroxy-Z', 4-dimethoxy-3-(3-methyl-2-butenyl)-4'- (3-methyI-2-butenyloxy)chalcone.

16. A chalcone ether according to claim 1, 4- acetoxy-Z 6'-dimethoxy-3-( 3-methyl-2-butenyl)-4 3- methyl-2-butenyloxy)chalcone.

17. A chalcone ether according to claim I, 4,4'-bis- (3,7-dimethyl-2,6-octadienyloxy)chalcone.

18. A chalcone ether according to claim 1, 3'-methyl-4,4'-bis-(3,7-dimethyl-2,6-octadienyloxy)chalcone.

19. A chalcone ether according to claim I, 4'- hydroxy-4-methoxy-3'( 3-methyl-2-butenyl )-2-( 3 ,7- dimethyl-2,6-octadienyloxy)chalcone.

20. A chalcone ether according to claim 1, 4hydroxy-Z ,4-dimethoxy-3 3-methyl-2-butenyl )-2-( 3,7- dimethyl-2,-octadienyloxy)chalcone.

21. A chalcone ether according to claim I, 2,4,4'- trimethoxy-3-(3-methyl-2-butenyl)-2-(3,7-dimethyl- 2,6-octadienyloxy)chalcone. 

1. A CHALCONE ETHER REPRESENTED BY THE FORMULA (I)
 2. A chalcone ether according to claim 1, 4,4''-bis-(3-methyl-2-butenyloxy)chalcone.
 3. A chalcone ether according to claim 1, 2,4''-bis-(3-methyl-2-butenyloxy)chalcone.
 4. A chalcone ether according to claim 1, 3,4''-bis-(3-methyl-2-butenyloxy)chalcone.
 5. A chalcone ether according to claim 1, 2''-hydroxy-4,4''-bis-(3-methyl-2-butenyloxy)chalcone.
 6. A chalcone ether according to claim 1, 2''-hydroxy-2,4''-bis-(3-methyl-2-butenyloxy)chalcone.
 7. A chalcone ether according to claim 1, 2''-methoxy-4,4''-bis-(3-methyl-2-butenyloxy)chalcone.
 8. A chalcone ether according to claim 1, 4''-hydroxy-3''-(3-methyl-2-butenyl)-4-(3-methyl-2-butenyloxy)chalcone.
 9. A chalcone ether according to claim 1, 2'',4''-dihydroxy-3''-(3-methyl-2-butenyl)-4-(3-methyl-2-butenloxy)chalcone.
 10. A chalcone ether according to claim 1, 2'',4''-dihydroxy-5''-(3-methyl-2-butenyl)-4-(3-methyl-2-butenyloxy)chalcone.
 11. A chalcone ether according to claim 1, 2'',4''-diacetoxy-2-methyl-3''-(3-methyl-2-butenyl)-4-(3-methyl-2 -butenyloxy)chalcone.
 12. A chalcone ether according to claim 1, 4-hydroxy-3-(3-methyl-2-butenyl)-4''-(3-methyl-2-butenyloxy)chalcone.
 13. A chalcone ether according to claim 1, 2'', 4-dihydroxy-3-(3-methyl-2-butenyl)-4''-(3-methyl-2-butenyloxy)chalcone.
 14. A chalcone ether according to claim 1, 2''-hydroxy-4-methoxy-3-(3-methyl-2-butenyl)-4''-(3-methyl-2 -butenloxy)chalcone.
 15. A chalcone ether according to claim 1, 2-hydroxy-2'', 4-dimethoxy-3-(3-methyl-2-butenyl)-4''-(3-methyl-2-butenyloxy)chalcone.
 16. A chalcone ether according to claim 1, 4-acetoxy-2'', 6''-dimethoxy-3-(3-methyl-2-butenyl)-4''(3-methyl-2-butenyloxy)chalcone.
 17. A chalcone ether according to claim 1, 4,4''-bis-(3,7-dimethyl-2,6-octadienyloxy)chalcone.
 18. A chalcone ether according to claim 1, 3''-methyl-4,4''-biS-(3,7-dimethyl-2,6-octadienyloxy)chalcone.
 19. A chalcone ether according to claim 1, 4''-hydroxy-4-methoxy-3''(3-methyl-2-butenyl)-2-(3,7-dimethyl-2,6 -octadienyloxy)chalcone.
 20. A chalcone ether according to claim 1, 4''hydroxy-2'',4-dimethoxy-3''-(3-methyl-2-butenyl)-2-(3,7-dimethyl-2,6 -octadienyloxy)chalcone.
 21. A chalcone ether according to claim 1, 2'',4,4''-trimethoxy-3''-(3-methyl-2-butenyl)-2-(3,7-dimethyl-2,6 -octadienyloxy)chalcone. 